The problem underlying the present invention was to provide a new process adapted for production in the plant, giving a reproducible high enantiomeric yield and a high optical purity.
Ropivacaine hydrochloride monohydrate is the generic name for the compound (S)-(-)-1-propyl-2',6'-pipecoloxylidide hydrochloride monohydrate, which compound is a local anesthetic described in EP 0 239 710. It is prepared by adding water and hot acetone to ropivacaine hydrochloride whereafter the desired product is crystallized. The process for the preparation of the starting material ropivacaine hydrochloride, is described in EP 0 151 110.
GB patent no. 1,180,712 discloses a process for the preparation of levo-1-n-butyl-2',6'-pipecoloxylidide. Said process includes a first step of resolving dl-2',6'-pipecoloxylidide, whereby dl-2',6'-pipecoloxylidide is reacted with 0,0-dibenzoyl-d-tartaric acid and thereafter the resulting mixture of diastereoisomeric 0,0-dibenzoyl-d-tartrates is reacted with boiling acetone, the acetone-insoluble dextro-2',6'-pipecoloxylidide salt is separated and the levo-2',6'-pipecoloxylidide salt is isolated from the acetone solution. However, the described process is intricate and includes isolating the product from hot acetone, i.e. it is a plain method for laboratories which could not be used for production in the plant.
The idea of using a resolution method to obtain the longer acting single enantiomers of the local anesthetics mepivacaine and bupivacaine was published in J Med Chem 14:891-892, 1971. A mixture of 2',6'-pipecoloxylidide was treated with dibenzoyl-L-tartaric acid monohydrate whereby isopropanol was added separating the isopropanol-insoluble enantiomer whereafter the desired enantiomer was isolated. Using isopropanol does not give a crystallisation system which is stable during the time required for production in the plant. This is because the solution is supersaturated with the undesired enantiomer, and thus a crystallization of the wrong shape could easily be started by small disturbances which means that isopropanol is not suitable to use for production in large scale.
In Acta Chem Scand B41: 757-761, 1987 it is described to use isopropanol in combination with various water-contents for the resolution step. These combinations gave varying yield and quality. Also the combination of isopropanol and water gave a crystallisation system not enough stable for production in the plant.